Project Summary
Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) approved by FDA for treatment of
estrogen receptor positive (ER+) early stage and advanced breast cancer. Although TMX is the mainstay
of breast cancer treatment, 20-30% of of breast cancer patients exhibit an existing or developing
resistance to TMX therapy with cancer metastsis, by poorly understood mechanisms. Therefore an
understanding of molecular mechanisms and predictive correlates of these pathological effects
associated with TMX treatment will help design improved adjuvant therapies to overcome TMX resistance
and related pathologies for effective management of breast cancer. In this regard, we recently reported
that TMX induces robust formation of neutrophil extracellular traps (NETs), which are DNA fibrils exuded
from activated neutrophils that can trap and kill extracellular pathogens to boost antimicrobial host
defense in chronic granulomatous disease. However, unconstrained NET release has been linked to
several immunopathologies including cancer. Because breast cancer patients are typically prescribed
TMX as the first or second line therapy, we hypothesize that long-term TMX treatment induces NET
formation in these patients, which correlates with and can account for TMX resistance and cancer
metastasis. This hypothesis is supported by our preliminary data showing that the extent of NET formation
in breast cancer patients is directly proportional to the duration of TMX treatment and that NETs purified
from TMX treated breast cancer patients increase cancer cell survival. Leveraging a characterized large
cohort of breast cancer patients treated with TMX at MD Anderson Cancer Center, in this clinical
exploratory study we will quantify and characterize NETs in blood samples from pre- and post-
menopausal women diagnosed with ERa+ breast cancer receiving TMX therapy for varying durations of
time, and correlate it with clinical data on co-morbidities, cancer metastasis and recurrence (Aim 1a). We
will examine the phenotype and transcriptional landscape of neutrophils from these patients with a focus
on TMX-activated NET pathway dentified by us (Aim 1b). Lastly, we will determine the direct impact of
TMX-induced NETs on survival and transcriptional reprogramming of breast cancer cells in response to
tamoxifen exposure (Aim 2). Because the NET-inducing action of TMX in breast cancer patients and its
impact on breast cancer cells as it relates to tamoxifen resistance is completely unknown, our proposed
studies will provide novel insights into the mechanism of tamoxifen resistance and future therapeutic
opportunities to prevent cancer metastasis and other adverse effects of TMX.